The broad hypothesis of this proposal is that age-related hormone change affects age-related cognitive change. The ultimate goat is to attenuate brain aging and cognitive deterioration via hormonal modulation. There is evidence that hormone loss at menopause exacerbates cognitive decline and contributes to the increased prevalence of Alzheimer's disease (AD) in women, and that hormone therapy attenuates these effects. However, recent studies found that combined estrogen/progesterone therapy increased dementia risk in women. Other research found that combined treatment was detrimental to cognitive performance, while estrogen-only was not. We hypothesize that estrogen alone benefits cognition, and that progesterone alters estrogen's effects resulting in a negative outcome of combined hormone treatment. We recently found that ovariectomy (Ovx) was detrimental to cognition in young rats, but enhanced cognition in aged rats. Since progesterone was elevated in aged rats, we hypothesized that removal of elevated progesterone contributed to enhanced scores. Our next study showed that, indeed, progesterone treatment reversed the cognitive enhancing effect of Ovx in aged rats. These findings, taken with data indicating that progesterone enhanced cognitive profiles in young Ovx rats, leads us to hypothesize that Ovx and progesterone have different effects on the young vs aged brain. Although studies have tested the effects that estrogen alone has on the brain and cognition, few studies have tested the effects of progesterone alone or in conjunction with estradiol. This is the goal of the current grant proposal. Specific Aim I tests the hypothesis that progesterone is detrimental to memory and associated neural parameters, and that such effects depend on age. Experiment 1 will evaluate the effects of Ovx and Ovx plus progesterone treatment at ages ranging from adult to aged. This will better define the age at which Ovx transitions from detrimental to beneficial for spatial memory. Specific Aim 2 tests the hypothesis that progesterone counteracts the effects of estrogen on memory and neural parameters related to age-associated cognitive change. Experiment 2 will compare the effects of estrogen to estrogen/progesterone therapy at an age where estrogen enhances cognition. In both studies, a maze battery will evaluate spatial and non-spatial working and reference memory, yielding a thorough cognitive profile. This will be followed by assessment of amyloid precursor protein (APP) processing and neurotrophin levels, both of which are altered by age and hormones. These studies are the next step in elucidating ovarian hormone influences on cognition during aging and will direct future studies. They may yield insight into why several clinical trials indicate that estrogen alone benefits cognition and AD risk, while estrogen/progesterone does not. The proposed research will also detail the mnemonic and neural functions that are compromised with age, ovarian hormone loss, and therapies of estrogen alone or estrogen/progesterone combinations.